Microbes that are successful at colonizing mucosal surfaces have highly developed strategies for evading host clearance mechanisms. We have shown that the pneumococcus, a major pathogen that colonizes the majority of young children, is able to persist in its niche in the human nasopharynx despite induction of type specific antibody during carriage. One such pneumococcal mechanism to subvert mucosal immunity is the expression of a human immunoglobulin A1 (lgA1) specific protease. The frequency of neutralizing antibody to this protease and the presence of other isotypes and subclasses of immunoglobulin in the airway suggest that pneumococci have additional mechanisms contributing to persistence despite the antibody response. Through the analysis of phenotypic variants, we have shown that colonizing pneumococci have 1) upregulation of three exoglycosidases, which remove the terminal trisaccharides from extensively glycosylated secretory IgA, and 2) increased levels of cell surface choline binding protein A (CbpA), which binds to human secretory component (hSC). In addition, our preliminary data from microarray comparisons of host gene expression during colonization in a murine model suggests that pneumococci inhibit expression of secretory immunoglobulin by selective suppression of local plasma cell activity. Based on these observations, we will explore novel mechanisms used by the pneumococcus to evade clearance by secretory immunoglobulin. In specific aim #1, we will determine the combined effect of pneumococcal exoglycosidases that target IgA and hSC on the function of mucosal immunoglobulin. In specific aim #2, we will determine whether binding of hSC diminishes the clearance function of secretory antibody and explore the role of the interaction of hSC with the integrin Mac-1 on professional phagocytes in this inhibitory effect. In specific aim #3, we will examine the effect of pneumococcal colonization on plasma cell activity and define pneumococcal factors that affect the production of secretory immunoglobulin.